Breast Cancer-Targets and Therapy
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2026
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IF 3.6
Peng Chen,Jiapeng Xu,Yulong Liang,Jinghui Mu,Wenjing Feng,Jiaming Liu,Bolun Li
Objective To investigate the biological function of SLC2A9 in triple-negative breast cancer (TNBC) and its molecular mechanism of influencing TNBC cells by regulating uric acid (UA) metabolism.Methods Bioinformatics analysis was performed to screen genes intersecting TNBC and UA metabolism pathways. TNBC cell lines were cultured in vitro, followed by the establishment of SLC2A9 overexpression and knockdown models. Subsequently, the levels of intracellular and extracellular UA were quantified. Cell proliferation, apoptosis, migration, and invasion capabilities were assessed using CCK-8, plate cloning, flow cytometry apoptosis analysis, scratch assay, and Transwell assays. Western blot analysis evaluated the expression of apoptosis-related proteins and UA metabolism proteins.Results SLC2A9 was significantly downregulated in TNBC tissues and most cell lines. SLC2A9 overexpression inhibited TNBC cell proliferation, migration, and invasion while promoting apoptosis. It also increased extracellular UA secretion and reduced intracellular UA accumulation. Conversely, SLC2A9 knockdown or probenecid treatment reversed these phenotypes. SLC2A9 exerts its effects by upregulating XDH, downregulating ABCG2, and modulating mitochondrial apoptosis pathway protein expression.Conclusion SLC2A9 regulates the malignant phenotype of TNBC by altering the levels of UA inside and outside the cell. Its anticancer activity depends on UA transport function, making it a promising prognostic biomarker and novel metabolic therapeutic target for TNBC.
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Hongxin Cai,Yu Zhang,Jingyu Wang,Yufeng Deng,Jiangyuan Liu,Zhiguo Wu,Dejian Cao,Zhiying Song,Lele Wang,Baogang Xie
Ethnopharmacological relevance Liuwei dihuang pills is a famous Traditional Chinese Medicine with various anti-cancer properties. Over 50 pharmaceutical manufacturers produce Liuwei dihuang pills in China and an estimated millions of people around the world orally take it every day. D-glucaro-1,4-lactone (1,4-GL) was quantified to be about 12.0 mg/g in Liuwei dihuang pills and a primary bioactive component of it inhibiting the activity of β-glucuronidase in vivo. 1,4-GL can prevent and effectively inhibit various types of cancer. However, its exact mechanism of action remains unknown. The study would justify the traditional usage of Liuwei dihuang pills against cancers. Aim of the study 1,4-GL, a bioactive ingredient derived from Liuwei dihuang pills, a famous Traditional Chinese Medicine, could delay the progression of diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in rats. The mechanism underpinning the effect, however, remains poorly understood. Materials and methods Healthy and HCC rats were treated with or without 1,4-GL (40.0 mg/kg) and 1 HNMR-based metabonomic analysis was employed. 10 metabolites in uric acid pathway were quantitatively determined by UPLC-MS/MS. The expression of xanthine dehydrogenase (XDH), SLC2A9 mRNA, and SLC2A9 protein was determined using RT-qPCR and Western Blot. The effect of 1,4-GL on HCC-LM3 cells was verified in vitro. The alterations of ROS activity, SLC2A9 and XDH gene levels were observed in NCTC-1469 cells induced by lipopolysaccharide (LPS) after 1,4-GL treatment. Results After the intervention of 1,4-GL, improved pathological morphology, liver lesions in HCC rats was observed with restored serum levels of AFP, AST, ALP, γ-GGT and Fisher's ratio. Hepatic metabonomics revealed that puring metabolism were significantly regulated by 1,4-GL in HCC rats. Uric acid, xanthine and hypoxanthine levels were quantified by UPLC-MS/MS and found to be nearly restored to control levels after 1,4-GL treatment in HCC rats. Changes in xanthine oxidase activity, XDH mRNA expression, and SLC2A9 mRNA and protein expression were also reversed. 1,4-GL treatment in LM3 HCC cells were consistent with the results in vivo. Furthermore, oxidative stress indicators such as T-SOD, GSH, CAT and MDA in serum and liver were improved after HCC rats treated with 1,4-GL. In vitro, 1,4-GL was observed to reduce lipopolysaccharide-induced ROS levels in NCTC-1469 cells with enhanced mRNA and protein expression of SLC2A9 and decreased mRNA level of XDH. Conclusion The protective effects of 1,4-GL against DEN-induced HCC by reducing uric acid and ROS levels due to down-regulation of uric acid production and up-regulation of SLC2A9 expressions. 1,4-GL may represent a novel treatment that improves recovery from HCC by targeting uric acid-ROS pathway.
研究领域:
药理学
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肿瘤学
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传统中药
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分子生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）